Journal of Neuroscience最新文献

Baker-Gordon syndrome (BAGOS) is a neurodevelopmental disorder (NDD) linked to a series of de novo mutations in the synaptic vesicle protein, Synaptotagmin-1 (SYT1). SYT1 is the major calcium sensor for synaptic transmission, and therefore a key molecule in neuronal communication. Several approaches have been used to reveal the underlying molecular mechanisms that lead to BAGOS pathology. While the murine genetic deletion, loss-of-function approach has proven valuable for modeling human diseases, human-induced pluripotent stem cells (hiPSCs) offer a powerful new strategy. In this study, we compare the phenotypes of BAGOS-associated SYT1 mutant variants in murine and human neuron models of either sex. In the well-established murine SYT1 knock-out (KO) model, we found that although all SYT1 mutant variants were correctly localized to the synaptic compartment, none could effectively rescue synaptic transmission. To examine the phenotype of BAGOS-associated SYT1 mutations in the context of human neurons, we generated a SYT1 KO hiPSC line via CRISPR/Cas9 gene editing and used this to derive neurons. As in mouse neurons, SYT1 KO in hiPSCs-derived human neurons strongly impairs synchronous release. Surprisingly, fast synaptic transmission could be rescued to varying extents in the human SYT1 KO model using BAGOS SYT1 mutants. However, overexpression of BAGOS SYT1 mutants in either WT mouse neurons or hiPSC-derived human neurons, a condition closer to the heterozygotic genotype of patients, revealed a dominant-negative effect of the mutant proteins. Our findings suggest that impaired neurotransmitter release efficacy caused by mutations in synaptic proteins may contribute to NDD pathophysiology.

Our visual system can recognize patterns across many spatial scales. A fundamental assumption in visual neuroscience is that this ability relies on the putative scale-invariant properties of receptive fields (RFs) in early vision, whereby the spatial area over which a visual neuron responds is proportional to the spatial scale of information it can encode (i.e., spatial frequency, SF). In other words, the resolution of spatial sampling of a RF is assumed to be constant in the visual cortex. However, this assumption has gone untested in the human visual cortex. To address this, we leveraged model-based fMRI techniques that characterize the spatial tuning and SF preferences of cortical subpopulations sampled within a voxel across eight participants (five females, three males). We find that the voxel-wise ratio between peak SF tuning and RF size-expressed as "cycles per RF"-remains constant across visual areas V1, V2, and V3, suggesting that, at the population level, SF preferences are inversely proportional to the RF size, a tenet of scale invariance in early human vision.

Visuospatial attention is key for parsing visual information and selecting targets to look at. Based on regimented laboratory tasks, it is now well-established that three types of mechanism determine when and where attention is deployed; these are stimulus-driven (exogenous), goal-driven (endogenous), and history-driven (reflecting recent experience). It is unclear, however, how these distinct attentional signals interact and contribute in visual environments that are more akin to natural scanning, when stimuli may change rapidly and no fixation requirements are imposed. Here, we investigate this via a gamified task in which participants (male and female) make continuous saccadic choices at a rapid pace-and yet, perceptual performance can be accurately tracked over time as the choice process unfolds. The results reveal unequivocal markers of exogenous capture toward salient stimuli; endogenous guidance toward valuable targets and relevant locations; and history-driven effects, which produce large, involuntary modulations in processing capacity. Under dynamic conditions, success probability is dictated by temporally precise interplay between different forms of spatial attention, with recent history making a particularly prominent contribution.

The basal ganglia play a key role in visual perceptual decisions. Despite being the primary target in the basal ganglia for inputs from the visual cortex, the posterior striatum's (PS) involvement in visual perceptual behavior remains unknown in rodents. We reveal that the PS direct pathway is largely segregated from the dorsomedial striatum (DMS) direct pathway, the other major striatal target for visual cortex. We investigated the role of the PS in visual perceptual decisions by optogenetically stimulating striatal medium spiny neurons in the direct pathway (D1-MSNs) of male and female mice performing a visual change-detection task. PS D1-MSN activation robustly biased visual decisions in a manner dependent on visual context, timing, and reward expectation. We examined the effects of PS and DMS direct pathway activation on neuronal activity in the superior colliculus (SC), a major output target of the basal ganglia. Activation of either direct pathway rapidly modulated SC neurons, but mostly targeted different SC neurons and had opposite effects. These results demonstrate that the PS in rodents provides an important route for controlling visual decisions, in parallel with the better known DMS, and with distinct anatomical and functional properties.Significance Statement The rodent posterior striatum (PS) is strongly innervated by visual cortex and thalamus, but its functional role in visual behavior has not been explored. We show that the PS initiates a direct pathway through the basal ganglia that is anatomically distinct from the more commonly studied dorsomedial striatum (DMS). Activating the PS direct pathway selectively biases decisions for expected, valued visual events. We also show that both DMS and PS direct pathways modulate neuronal activity in the superior colliculus, a structure critical for visual processing and sensorimotor function, and preferentially modulate collicular units with properties relevant in the visual detection task. These findings identify a distinct and novel circuit through the basal ganglia for controlling visually guided perceptual decisions.

Reading is a fundamental skill for communication, learning, and daily life. Alexia, an acquired reading disorder typically caused by left hemisphere stroke, impairs both oral and silent word reading. However, most research and clinical assessments focus on oral reading. Functional imaging studies in typical readers suggest partly shared and partly distinct neural bases of oral versus silent reading, but this has never been assessed in a lesion study. We examined oral word reading and silent word recognition, measured by a lexical decision task, in 85 chronic left hemisphere stroke survivors (46 males, 39 females), comparing efficiency scores combining speed and accuracy to those of 69 neurologically healthy adults (36 males, 33 females). The stroke group had greater deficits in oral reading than lexical decision. Performance on the two tasks was highly correlated suggesting shared substrates, albeit with considerable unexplained variance. Support vector regression-based lesion-symptom mapping localized lesions associated with deficits in the two tasks. Oral reading deficits were associated with lesions to the superior temporal and supramarginal gyri, and the rolandic operculum after controlling for lexical decision performance. Lexical decision deficits were linked to lesions in angular gyrus, even after controlling for oral reading performance. A novel conjunction analysis found that lesions of angular and middle temporal gyri, extending into ventral occipitotemporal cortex, affected performance on both tasks, suggesting shared neural substrates. These findings suggest that neurocognitive bases of silent reading and reading aloud are partly shared and partly distinct. Alexia assessments should include both silent and oral reading tasks.Significance Statement Silent reading is essential for daily life, but has received less attention than oral reading in research on acquired reading deficits, i.e., alexia. While functional imaging suggests partially distinct activation patterns for oral and silent reading, lesion-symptom mapping offers a critical method for identifying brain regions necessary for task performance. This is the first lesion mapping study to compare oral and silent reading within the same individuals. Using lexical decision as a proxy for silent reading, we found partly shared and partly distinct neural substrates for silent versus oral reading. These findings reveal overlapping but differentially weighted neural systems and underscore the need to assess silent reading alongside oral reading when assessing alexia.

Schema memory refers to generalized knowledge that is formed across multiple episodes containing regularities. Schema memory is thought to be formed in an active systems consolidation process that transforms individual episodic representations into neocortically anchored schema representations and that is facilitated by sleep. Here we show in rats that sleep is indeed critical for the emergence of a new schema memory. Male rats (n = 20) were trained on an elaborated version of the object-place recognition (OPR) task, which allowed for abstraction of a spatial rule across eight encoding episodes spaced 20 minutes apart without intermittent sleep. During each episode, animals freely explored two objects in an open-field arena. Following the encoding phase, animals either slept or were kept awake for two hours, after which they remained undisturbed for 22 hours before schema memory for the spatial rule was assessed. Only animals that slept during the two-hour post-encoding window exhibited schema memory. Prior knowledge conflicting with the spatial rule prevented schema memory formation. c-Fos expression assessed at retrieval indicated that successful schema recall was supported by a more sparsely activated yet highly interconnected network comprising, amongst others, medial prefrontal cortex and hippocampus. Our findings highlight the critical role of immediate post-encoding sleep in forming new spatial schema memory.Significance Statement Schema representations integrate regularities abstracted from multiple episodes. Whether and how the formation of schema representations benefit from sleep is still unclear, partly because evoking abstraction processes across episodes within a single wake period in animal models is challenging. Using an object-place recognition (OPR) - based schema memory task, we show for the first time in rats that sleep critically supports schema memory formation. Rats that slept, but not those kept awake for 2 hours after encoding the eight task episodes, expressed schema memory 24 hours later. Schema recall after sleep was associated with a sparse but distinctly more coordinated network activation, mainly comprising medial prefrontal cortex and hippocampus. Our findings highlight sleep's role in newly forming distributed spatial schema representations.

Our daily interactions with the world are shaped by sensory expectations informed by context and prior experiences, which in turn influence how we allocate our attention. Prominent predictive coding models suggest that sensory expectancy and attention interact but disagree on the precise mechanisms. One possibility is that the Ventral Attention Network (VAN) may play a role by facilitating attentional reorienting when expectancy is violated. To test this in humans (23 males and 43 females), we employed an auditory-visual trial-by-trial cueing paradigm in three experiments integrating EEG and fMRI to investigate the VAN's role in violations of cross-modal expectancy. Behavioral results showed faster responses to expected targets, confirming the efficacy of cue-induced expectations in orienting attention to the expected target modality. EEG analyses revealed differences in early (∼100 ms latency) event-related potentials (ERPs) to both auditory and visual stimuli when expectations were violated. Unexpected stimuli elicited significantly larger early-latency negative ERPs, across both modalities. Source localization of these ERPs and subsequent fMRI evidence revealed activation in the right VAN. Functional connectivity analyses showed greater coupling between VAN regions and sensory cortices, with modality-specific pathways involving superior temporal gyrus (STG) for auditory and fusiform gyrus (FG) for visual targets. These findings demonstrate that expectancy violations recruit the VAN to reorient attention and resolve sensory conflict. By coordinating top-down control and bottom-up sensory input, the VAN supports adaptive responses to unexpected stimuli. This work advances our understanding of predictive processing in multisensory perception and highlights the VAN's central role in flexible cognitive control.Significance Statement This study shows how expectations regarding sensory modalities might cause the brain to reorient attention. The study shows that during cross-modal expectation violations, the right-lateralized Ventral Attention Network (VAN), which includes the temporoparietal junction and inferior frontal gyrus, is quickly engaged using EEG and fMRI. Early ERP differences and higher VAN activation were evoked by unexpected visual and auditory stimuli, which also boosted connection to sensory areas. These results demonstrate the VAN's critical function in adaptive attention across modalities and further our understanding of prediction processing. The findings have significant implications for sensory integration models, attention models, and disorders involving expectation and control deficiencies.

Recent studies suggest some hippocampal (HC) neurons respond to passively presented sounds in naive subjects, but the specificity and prevalence of these responses remain unclear. We used Neuropixels probes to record unit activity across layers in mid-ventral HC and auditory cortex (ACtx) of awake, untrained mice (male and female) while presenting diverse sounds at typical environmental levels (65-70 dB SPL). A subset of HC neurons exhibited reliable, short latency responses to passive sounds, including tones and broadband noise. HC units showed evidence of tuning for tone frequency but not spectrotemporal features in continuous dynamic moving ripples. Across sound types, HC responses overwhelmingly occurred at stimulus onset; they quickly adapted to continuous sounds and did not respond at sound offset. Among all sounds tested, broadband noise was most effective at driving HC activity. Spectral manipulations indicated response prevalence scaled with increasing spectral bandwidth and density. Similar responses were also observed for visual flash and contrast-modulated noise movies, although these were less common than for broadband noise. Sound-evoked face movements, quantified by total face motion energy (FME), correlated with population-level HC activity. However, many individual units responded regardless of FME strength, suggesting both auditory and motor-correlated inputs. Together, our results show that abrupt sound onsets are sufficient to activate many HC neurons in the absence of learning or behavioral engagement. This supports a role for HC in detecting salient environmental changes and supports the idea that auditory inputs contribute directly to HC function.